Gamma -herpesviruses such as Kaposi's sarcoma-associated herpesvirus (KSHV; also known as HHV8) and murine gamma herpesvirus 68 (MHV-68) are DNA viruses involving both latent and lytic programs during their interactions with host. KSHV infection leads to an AIDS defining cancer that represents a significant clinical problem. Despite the positive outcome of HAART on Kaposi Sarcoma, little is known about the role of KSHV-specific host immunity in disease progression. The main goal of this project is to understand the role of non-coding RNAs in modulating gamma-herpesvirus life cycle and in regulating host-pathogen interactions. The human host is invaded by a wide range of microbial pathogens and has evolved a number of defensive mechanisms to survive these infections. In addition to adaptive immunity, it is becoming increasingly clear that innate immunity plays an important role in protecting host organisms from infections. To achieve persistent infections, pathogens have co-evolved with host to devise mechanisms to successfully replicate and evade host innate immune system. MicroRNAs (miRNAs) are 18-24 nucleotide single stranded non-coding RNA, usually generated from noncoding regions of gene transcripts, bind to target mRNAs by base-pairing, and guide posttranscriptional repression of these target mRNAs. A growing number of recent studies support the hypothesis that viruses encode miRNAs that assist viruses to evade immune responses in infected cells and to regulate different phases of viral life cycle. In addition to viral miRNAs, recent studies show that host cells respond to viral infections by changing the expression of cellular miRNAs that could be a part of innate immune response to viral infections. Understanding the RNA-based mechanisms to boost immune system will directly impact the design of new strategies for antiviral and cancer vaccines. Our project will investigate the role of host non-coding RNAs and RNP complexes including RNAi machinery in regulating interactions between a host and MHV-68/KSHV and in evading gammaherpesvirus innate immune mechanisms. We will employ highly innovative, collaborative, multidisciplinary approaches, and support from state of the art cores facilities to address these fundamental questions in an emerging field of biology.